(S)-(+)-3-(aminomethyl)-5-methyl-hexanoic acid or (S)-pregabalin (1) is an anticonvulsive drug manufactured and marketed by Pfizer. In its first full year on the market this drug achieved sales in excess of 1 billion US dollars.

In addition to its use as an anticonvulsive agent, pregabalin has also been indicated as a medicament in the treatment of anxiety, neuropathic pain and pain in patients with fibromyalgia.
Two existing syntheses of (S)-(+)-3-(aminomethyl)-5-methyl-hexanoic acid proceed through the meso-anhydride 3-isobutylglutaric anhydride (2).

U.S. Pat. No. 5,616,793 describes aminolysis of 2 with aqueous ammonia as illustrated in Scheme 1. The resultant racemic amide (A) is resolved by reacting it with (R)-(+)-α-phenylethylamine to yield (R)-(−)-3-(carbamoylmethyl)-5-methyl hexanoic acid, which is in turn subjected to a Hofmann rearrangement to afford (S)-pregabalin. This process suffers in that it is wasteful as the unwanted enantiomer of intermediate A is discarded, and the chiral resolving agent (R)-(+)-α-phenylethylamine has to be employed is substantial quantities and subsequently removed from the reaction.
U.S. Pat. No. 7,462,738 discloses the asymmetric alcoholysis of 3-isobutylglutaric anhydride to afford hemiester B. The overall synthetic strategy is outlined in Scheme 2. Enantioselective alcoholysis of 3-isobutylglutaric anhydride is obtained utilising either a chiral alcohol or an achiral alcohol in combination with a chiral amine. Amidation of enantioenriched hemiester B with aqueous ammonia yields (R)-(−)-3-(carbamoylmethyl)-5-methyl hexanoic acid and a Hofmann rearrangement affords (S)-pregabalin.

In order to achieve good enantioselectivity, the process of U.S. Pat. No. 7,462,738 necessitates that the chiral alcohol or chiral amine/achiral alcohol combination employed in the alcoholysis step be utilised in an appreciable excess relative to the starting material 3-isobutylglutaric anhydride, i.e. greater than 1:1. In all cases the chiral amine must be employed in stoichiometric amounts. Such an approach is inefficient and costly. Furthermore, exceedingly low temperatures of −50° C. or −78° C. are required for acceptable enantioinduction in the alcoholysis step.

Notwithstanding the state of the art it would still be desirable to provide alternative enantioselective synthetic methods for preparing 3-(aminomethyl)-5-methyl-hexanoic acid. Ideally, such methods would provide for high enantioselectivity at ambient temperature and enantioinduction would be achievable utilising a chiral catalyst in sub-stoichiometric quantities relative to the starting reagent, thereby affording an efficient and economic synthetic process.